THE INNER TUBE OF LIFE

S PECIAL S ECTION
SPECIAL/REVIEW

Host-Bacterial Mutualism
in the Human Intestine
Fredrik Bäckhed,* Ruth E. Ley,* Justin L. Sonnenburg, Daniel A. Peterson, Jeffrey I. Gordon.
The distal human intestine represents an anaerobic bioreactor programmed with an Bacteroides (CFB) (e.g., the genus Bacteroides)
enormous population of bacteria, dominated by relatively few divisions that are and the Firmicutes (e.g., the genera Clostridium
highly diverse at the strain/subspecies level. This microbiota and its collective ge- and Eubacterium)—each comprise È30% of
nomes (microbiome) provide us with genetic and metabolic attributes we have not bacteria in feces and the mucus overlying the
been required to evolve on our own, including the ability to harvest otherwise intestinal epithelium. Proteobacteria are com-
inaccessible nutrients. New studies are revealing how the gut microbiota has co- mon but usually not dominant (5). In com-
evolved with us and how it manipulates and complements our biology in ways that parison, soil (the terrestrial biosphere’s GI
are mutually beneficial. We are also starting to understand how certain keystone tract, where degradation of organic matter
members of the microbiota operate to maintain the stability and functional adapt- occurs) can contain 20 or more bacterial
ability of this microbial organ. divisions (6).
Our knowledge of the composition of the
The adult human intestine is home to an al- with anaerobic bacteria charged with the task adult gut microbiota stems from culture-based
most inconceivable number of microorga- of breaking down ingested polysaccharides, studies (7), and more recently from culture-

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nisms. The size of the population—up to 100
trillion—far exceeds that of all other micro-
bial communities associated with the body_s
surfaces and is È10 times greater than the
total number of our somatic and germ cells
(1). Thus, it seems appropriate to view
ourselves as a composite of many species
and our genetic landscape as an amalgam of
genes embedded in our Homo sapiens
genome and in the genomes of our affiliated
microbial partners (the microbiome).
Our gut microbiota can be pictured as a
microbial organ placed within a host organ:
It is composed of different cell lineages with
a capacity to communicate with one another
and the host; it consumes, stores, and redis-
tributes energy; it mediates physiologically
important chemical transformations; and it
can maintain and repair itself through self-
replication. The gut microbiome, which may
contain Q100 times the number of genes in
our genome, endows us with functional
features that we have not had to evolve
ourselves.
Our relationship with components of this
microbiota is often described as commensal
(one partner benefits and the other is appar-
ently unaffected) as opposed to mutualistic
(both partners experience increased fitness).
However, use of the term commensal gener-
ally reflects our lack of knowledge, or at least
an agnostic (noncommittal) attitude about the
contributions of most citizens of this microbi-
al society to our own fitness or the fitness of
other community members.
The guts of ruminants and termites are well-
studied examples of bioreactors Bprogrammed[
Center for Genome Sciences, Washington University
School of Medicine, St. Louis, MO 63108, USA.
*These authors contributed equally to this work.
.To whom correspondence should be addressed.
E-mail: jgordon@molecool.wustl.edu
the most abundant biological polymer on our
planet, and fermenting the resulting monosac-
charide soup to short-chain fatty acids. In these
mutualistic relationships, the hosts gain carbon
and energy, and their microbes are provided
with a rich buffet of glycans and a protected
anoxic environment (2). Our distal intestine
is also an anaerobic bioreactor that harbors
the majority of our gut microorganisms; they
degrade a varied menu of otherwise indigest-
ible polysaccharides, including plant-derived
pectin, cellulose, hemicellulose, and resistant
starches.
Microbiologists from Louis Pasteur and
Ilya Mechnikov to present-day scientists have
emphasized the importance of understanding
the contributions of this microbiota to human
health (and disease). Experimental and com-
putational tools are now in hand to compre-
hensively characterize the nature of microbial
diversity in the gut, the genomic features of
its keystone members, the operating principles
that underlie the nutrient foraging and sharing
behaviors of these organisms, the mechanisms
that ensure the adaptability and robustness of
this system, and the physiological benefits we
accrue from this mutualistic relationship. This
Review aims to illustrate these points and
highlight some future challenges for the field.
Microbial Diversity in the Human Gut
Bioreactor
The adult human gastrointestinal (GI) tract
contains all three domains of life—bacteria,
archaea, and eukarya. Bacteria living in the
human gut achieve the highest cell densities
recorded for any ecosystem (3). Nonetheless,
diversity at the division level (superkingdom
or deep evolutionary lineage) is among the
lowest (4); only 8 of the 55 known bacterial
divisions have been identified to date (Fig. 1A),
and of these, 5 are rare. The divisions that
dominate—the Cytophaga-Flavobacterium-
independent molecular phylogenetic approaches
based on sequencing bacterial ribosomal RNA
(16S rRNA) genes. Of the 9200,000 rRNA
gene sequences currently in GenBank, only
1822 are annotated as being derived from the
human gut; 1689 represent uncultured bacte-
ria. rRNA sequences can be clustered into
relatedness groups based on their percent se-
quence identity. Cutoffs of 95 and 98% iden-
tity are used commonly to delimit genera and
species, respectively. Although these values
are somewhat arbitrary and the terms ‘‘genus’’
and ‘‘species’’ are not precisely defined for
microbes, we use them here to frame a view of
human gut microbial ecology. When the se-
quences (n 0 495 greater than 900 base pairs)
are clustered into species, and a diversity
estimate model is applied, a value of È800
species is obtained (Fig. 2). If the analysis is
adjusted to estimate strain number (unique se-
quence types), a value of 97000 is obtained
(Fig. 2). Thus, the gut microbiota, which ap-
pears to be tremendously diverse at the strain
and subspecies level, can be visualized as a
grove of eight palm trees (divisions) with
deeply divergent lineages represented by the
fan(s) of closely related bacteria at the very
top of each tree trunk.
Diversity present in the GI tract appears
to be the result of strong host selection and
coevolution. For example, members of the
CFB division that are predominantly asso-
ciated with mammals appear to be the most
derived (i.e., farthest away from the common
ancestor of the division), indicating that they
underwent accelerated evolution once they
adopted a mutualistic lifestyle. Moreover, a
survey of GenBank reveals that several sub-
groups in CFB are distributed among differ-
ent mammalian species (Fig. 1B), suggesting
that the CFB-mammal symbiosis is ancient
and that distinct subgroups coevolved with
their hosts.

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S PECIAL S ECTION TTHHE EI INNNNE ERRTTUUBBE EOOF FL LI FI FE E
Fig. 1. Representation of the diversity of bacteria in the human intestine. (A)
Phylogenetic tree of the domain bacteria based on 8903 representative 16S
rRNA gene sequences. Wedges represent divisions (superkingdoms): Those
numerically abundant in the human gut are red, rare divisions are green, and
undetected are black. Wedge length is a measure of evolutionary distance from
the common ancestor. (B) Phylogenetic tree of the CFB division based on 1561
sequences from GenBank (9900 nucleotides) and their ecological context.
Wedges, major subgroups of CFB; symbols, source of the sequences [Earth,
environmental; cow, ruminants; rodent, rat and/or mouse; person, human GI
tract; others are termite, cockroach, worm (including hydrothermal), and pig].
Ratios are the number of sequences represented in the human gut relative to
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the total number in the subgroup; red, yellow, and black indicate majority,
minority, and absence of sequences represented in human GI tract, respectively.
(C) Phylogenetic (parsimony) tree of Bacteroides. Strains classified as B.
thetaiotaomicron based on phenotype are in red; 16S rRNA analysis did not
confirm this classification for all strains. Bacteroides spp. with sequenced
genomes are in bold. Black circles indicate nodes with high (970%) bootstrap
support (41). Scale bars indicate the degree of diversity (evolutionary distance)
within a division or subgroup [(A) and (B), respectively] in terms of the fraction of
the 16S rRNA nucleotides that differ between member sequences; in (C), the
evolutionary distance between organisms is read along branch lengths, where
scale indicates number of changes in 16S rRNA nucleotide composition.
SCIENCE www.sciencemag.org

The structure and composition of the gut
microbiota reflect natural selection at two
levels: at the microbial level, where lifestyle
strategies (e.g., growth rate and substrate
utilization patterns) affect the fitness of individ-
ual bacteria in a competitive ensemble; and at
the host level, where suboptimal functionality
of the microbial ensemble can reduce host
fitness. Microbial consortia whose integrated
activities result in a cost to the host will result
in fewer hosts, thereby causing loss of their
own habitat. Conversely, microbial consortia
that promote host fitness will create more hab-
itats. Thus, the diversity found within the
human GI tract, namely, a few divisions rep-
resented by very tight clusters of related bac-
teria, may reflect strong host selection for
specific bacteria whose emergent collective
behavior is beneficial to the host. This hypoth-
esis has two important implications: (i) A
mechanism exists to promote cooperation, and
(ii) the structure promotes functional stability
of the gut ecosystem.
To benefit the host, bacteria must be or-
ganized in a trophic structure (food web) that
aids in breaking down nutrients and provides
the host with energetic substrates. Cooperative
behavior that imposes a cost to the individual
while benefiting the community can emerge
within groups of bacteria (8) and can be main-
tained by group selection as long as consortia
are isolated and new consortia form periodi-
cally (e.g., new GI tracts). Furthermore, selec-
tion must act simultaneously at multiple levels
of biological organization (9). These criteria
are met in the human GI tract where new acts
of colonization occur at birth, with a small
founding population of noncheaters from the
mother, and selection occurs both at the mi-
crobial and host level.
Diversity is generally thought to be desir-
able for ecosystem stability (10). One im-
portant way diversity can confer resilience is
through a wide repertoire of responses to stress
[referred to as the insurance hypothesis (11)].
In man-made anaerobic bioreactors used to
treat wastewater (a system analogous to the
gut but where no host selection occurs), rates
of substrate degradation can remain constant,
whereas bacterial populations fluctuate chaot-
ically as a result of blooms of subpopulations
(12). Functional redundancy in the microbial
community ensures that key processes are un-
affected by such changes in diversity (13). By
contrast, in the human gut, populations are
remarkably stable within individuals (14),
implying that mechanisms exist to suppress
blooms of subpopulations and/or to promote
the abundance of desirable bacteria. A study
of adult monozygotic twins living apart and
their marital partners has emphasized the po-
tential dominance of host genotype over diet
in determining microbial composition of the
gut bioreactor (15). The role of the immune
system in defining diversity and suppressing
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subpopulation blooms remains to be defined.
One likely mediator of bacterial selection is
secretory immunoglobulin A (16).
The human gut is faced with a paradox:
How can functional redundancy be maintained
in a system with low diversity (few divisions
of bacteria), and how can such a system with-
stand selective sweeps in the form of, for ex-
ample, phage attacks? [The estimated 1200
viral genotypes in human feces (17) suggest
that phage attack is a powerful shaper of the
gut’s microbial genetic landscape (18, 19)].
Enough diversity of genome and transcrip-
tome must be represented at the subspecies
level to lend resilience to the gut ecosystem.
Ecological studies of macroecosystems have
shown that less diversity is required to main-
tain stability if individual species themselves
have a wide repertoire of responses (11). In the
Fig. 2. Taxon richness estimates for bacteria in
the human GI tract. Taxon richness estimates
(41) for varying levels of 16S rRNA sequence
identity, ranging from below the ‘‘genus’’ level
(95% identity), to the ‘‘species’’ level (98% iden-
tity), to the strain level (unique sequences).
Estimates are based on sequences available in
GenBank, annotated as derived from the
human GI tract, after alignment and clustering
into taxonomic units ranging from 80 to 100%
identity (41).
following section we discuss recent genome-
based studies exploring how a presumed key-
stone bacterial species in our gut is able to
adapt to (i) changing dietary conditions in
ways that should stabilize the microbiota’s
food web and (ii) changing immune and phage
selective pressures in ways that should stabi-
lize the ecosystem.
Bacteroides thetaiotaomicron—A Highly
Adaptive Glycophile
Bacteroides thetaiotaomicron is a prominent
mutualist in the distal intestinal habitat of
adult humans. It is a very successful glyco-
phile whose prodigious capacity for digesting
otherwise indigestible dietary polysaccharides
is reflected in the fully sequenced 6.3-Mb ge-
nome of the type strain (ATCC 29148; orig-
inally isolated from the feces of a healthy
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THE INNER TUBE OF LIFE
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adult human) (20). Its ‘‘glycobiome’’ contains
the largest ensemble of genes involved in ac-
quiring and metabolizing carbohydrates yet
reported for a sequenced bacterium, including
163 paralogs of two outer membrane proteins
(SusC and SusD) that bind and import starch
(21), 226 predicted glycoside hydrolases, and
15 polysaccharide lyases (22). By contrast, our
2.85-Gb genome only contains 98 known or
putative glycoside hydrolases and is deficient
in the enzyme activities required for degrada-
tion of xylan-, pectin-, and arabinose-containing
polysaccharides that are common components
of dietary fiber [we have one predicted enzyme
versus 64 in B. thetaiotaomicron (table S1)].
The carbohydrate foraging behavior of B.
thetaiotaomicron has been characterized dur-
ing its residency in the distal intestines (ceca)
of gnotobiotic mice colonized exclusively with
this anaerobe (23). Scanning electron micros-
copy studies of the intestines of mice main-
tained on a standard high-polysaccharide chow
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diet, containing xylose, galactose, arabinose,
and glucose as its principal monosaccharide
components, revealed communities of bacte-
ria assembled on small undigested or par-
tially digested food particles, shed elements
of the mucus gel layer, and exfoliated epi-
thelial lining cells (23). Whole-genome tran-
scriptional profiling of B. thetaiotaomicron
(23) disclosed that this diet was associated
with selective up-regulation of a subset of
SusC and SusD paralogs, a subset of glycoside
hydrolases (e.g., xylanases, arabinosidases, and
pectate lyase), as well as genes encoding en-
zymes involved in delivering the products of
mannose, galactose, and glucose to the glyco-
lytic pathway and arabinose and xylose to the
pentose phosphate pathway. In contrast, a sim-
ple sugar (glucose and sucrose) diet devoid of
polysaccharides led to increased expression of
a different subset of SusC and SusD paralogs,
glycoside hydrolases involved in retrieving
carbohydrates from mucus glycans, as well as
enzymes that remove modifications that make
these host glycans otherwise resistant to deg-
radation (O-acetylation of sialic acids and
sulfation of glycosoaminoglycans) (23).
These findings provide insights about
how functional diversity and adaptability are
achieved by a prominent member of the human
colonic microbiota (Fig. 3). Dining occurs on
particulate nutrient scaffolds (food particles,
shed mucus, and/or exfoliated epithelial cells).
For a bacterium such as B. thetaiotaomicron,
which lacks adhesive organelles, seating at the
‘‘dining table’’ is determined in part by the
repertoire of glycan-specific outer membrane–
binding proteins it produces, and this reper-
toire is itself shaped by the menu of available
glycans (23). Attachment to nutrient plat-
forms helps avoid washout from the intestinal
bioreactor, in much the same way as dense,
well-settling, granular biofilms help oppose
elimination from engineered (man-made) an-
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aerobic upflow bioreactors (24). Attachment
also presumably increases the efficiency of
oligo- and monosaccharide harvest by adapt-
ively expressed bacterial glycoside hydrolases
and their subsequent distribution to other mem-
bers of the microbiota whose niche overlaps
that of B. thetaiotaomicron. In this conceptual-
ization, microbial nutrient metabolism along
the length of the intestine is a summation of
myriad selfish and syntrophic relationships ex-
pressed by inhabitants of
these nutrient platforms.
Diversity in these micro-
habitats and mutualistic
cooperation among their
component species (includ-
ing the degree to which
sanctions must be applied
against cheats) are reflec-
tions of a dynamic interplay
between the available nu-
trient foundation and the
able to change its carbohydrate surface depend- transfer and mutation mechanisms endow
ing upon the nutrient (glycan) environment. strains of bacterial species with the (genet-
This could be part of a strategy for evading an ic) versatility necessary to withstand selec-
adaptive immune response. Whole-genome tive sweeps that would eradicate more clonal
genotyping studies of B. thetaiotaomicron iso- populations (26).
lates, with the use of GeneChips designed
from the sequenced genome of the type The Gut Microbiota as a ‘‘Host’’ Factor
strain, disclose that their CPS loci differ, That Influences Energy Storage
whereas their housekeeping genes are con- Comparisons of mice raised without expo-
served (25). Because selective sweeps are sure to any microorganisms [Germ-Free (GF)]
with those that have ac-
quired a microbiota since
birth [Conventionally Raised
(CONV-R)] have led to the
identification of numer-
ous effects of indigenous
microbes on host biology
(table S2), including en-
ergy balance. Young adult
CONV-R animals have 40%
more total body fat than
their GF counterparts fed the

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degree of flexible forag- same polysaccharide-rich
ing (niche breadth) ex- diet, even though CONV-R
pressed by microhabitat animals consume less chow
residents. Bacteroides per day (27). This obser-
spp., such as B. thetaio- vation might seem para-
taomicron, impart stabil- doxical at first but can be
ity to the gut ecosystem by explained by the fact that
having the capacity to turn the gut microbiota allows
to host polysaccharides energy to be salvaged from
when dietary polysaccha- otherwise indigestible dietary
rides become scarce. The polysaccharides (28). ‘‘Con-
highly variable outer chain ventionalization’’ of adult
structures of mucus and GF mice with cecal contents
epithelial cell surface gly- harvested from CONV-R
cans are influenced by donors increases body fat
host genotype and by mi- content to levels equiva-
crobial regulation of host lent to those of CONV-R
glycosyltransferase gene animals (27). The increase
expression. Coevolution Fig. 3. Lessons about adapative foraging for glycans obtained from B. thetaiotaomicron. reflects adipocyte hypertro-
of host glycan diversity (1) B. thetaiotaomicron does not have adhesive organelles. Without outer membrane phy rather than hyperplasia
polysaccharide-binding protein-mediated attachment to glycan-rich nutrient platforms,
and a large collection of it is at risk for being washed out from the intestinal bioreactor. Substrate access is and is notable for its rapid-
microbial glycoside hydro- limited under these conditions. (2) Small nutrient platforms are composed of undigested ity and sustainability (27).
lases that are regulated by or partially digested food particles (e.g., dietary fiber), shed host epithelial cells, and/or The mutualistic nature
nutrient availability pro- mucus fragments. These platform elements may be in dynamic equilibrium with one another of the host-bacterial rela-
vides insurance that the and with the mucus layer overlying the intestinal epithelium. Microbial fermentation of tionship is underscored by
‘‘system’’ (microbiota and otherwise indigestible polysaccharides in these platforms is made possible by induced mechanisms that underlie
expression of substrate-appropriate sets of bacterial polysaccharide-binding proteins and
host) can rapidly and effi- glycoside hydrolases. (3) Mesophilic methanogens drive carbohydrate utilization by removing this fat-storage phenotype.
ciently respond to changes products of fermentation (H and CO are converted to methane), thereby improving the Colonization increases glu-
2 2
in the diet, and maximize overall efficiency of energy extraction from polysaccharides. (4) When dietary polysac- cose uptake in the host intes-
energy harvest, without charides are scarce, B. thetaiotaomicron turns to host mucus by deploying a different set tine and produces substantial
having to undergo sub- of polysaccharide binding proteins and glycoside hydrolases. This adaptive foraging re- elevations in serum glucose
stantial changes in species flects the coevolved functional versatility of B. thetaiotaomicron’s glycobiome and the and insulin (27), both of
structural diversity of the host’s mucus glycans.
composition. Rather than which stimulate hepatic li-
minimizing genome size, pogenesis through their ef-
a keystone species such as B. thetaiotaomicron most likely to come from the immune system fects on two basic helix-loop-helix/leucine
has evolved an elaborate and sizable genome and phages, both of which respond to surface zipper transcription factors—ChREBP and
that can mobilize functionally diverse adapt- structures, the associated genes are likely to SREBP-1c (27, 29). Short-chain fatty acids,
ive responses. be the most diverse in the genome. Accord- generated by microbial fermentation, also in-
Diet-associated changes in the glycan forag- ingly, B. thetaiotaomicron has a remarkable duce lipogenesis (30). Triglycerides exported
ing behavior of B. thetaiotaomicron are also apparatus for altering its genome content. The by the liver into the circulation are taken up
accompanied by changes in expression of sequenced type strain contains a plasmid, 63 by adipocytes through a lipoprotein lipase
its capsular polysaccharide synthesis loci transposases, 43 integrases, and four homo- (LPL)–mediated process. The microbiota sup-
(CPS), indicating that B. thetaiotaomicron is logs of a conjugative transposon (20). Gene presses intestinal epithelial expression of a

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circulating LPL inhibitor, fasting-induced adi-
pose factor (Fiaf, also known as angiopoietin-
like protein-4) (27). Comparisons of GF and
conventionalized wild-type and Fiaf –/– mice
established Fiaf as a physiologically important
regulator of LPL activity in vivo and a key
modulator of the microbiota-induced increase
in fat storage (27).
The caloric density of food items is por-
trayed as a fixed value on package labels.
However, it seems reasonable to postulate
that caloric value varies between individual
‘‘consumers’’ according to the composition
and operation (e.g., transit time) of their in-
testinal bioreactors, and that the microbiota
influences their energy balance. Relatively
high-efficiency bioreactors would promote
energy storage (obesity), whereas lower effi-
ciency reactors would promote leanness
(efficiency is defined in this case as the
energy-harvesting and storage-promoting
potential of an individual’s microbiota rela-
tive to the ingested diet).
The idea that individual variations in
bioreactor efficiencies may be a significant
variable in the energy balance equation is
supported by several observations. First, in-
dividual variations in the composition of the
microbiota occur and are influenced by host
genotype (15). Second, small but chronic
differences between energy intake and ex-
penditure can, in principle, produce major
changes in body composition [e.g., if
energy balance is þ12 kcal/day, 90.45 kg
of fat could be gained per year if there are
no compensatory responses by the host; this
is the average weight increase experienced
by Americans from age 25 to 55 (31)]. Third,
the microbiota is a substantial consumer of
energy. One group estimated that individuals
on a ‘‘British Diet’’ must ferment 50 to 65 g
of hexose sugars daily to obtain the energy
required to replace the 15 to 20 g (dry
weight) of bacteria they excrete per day (32).
These considerations emphasize the need
to assess the representation of species with
large capacities for processing dietary poly-
saccharides, such as Bacteroides, in lean
versus morbidly obese individuals, and in
cohorts of obese individuals before, during,
and after weight reduction achieved by high-
polysaccharide/low-fat versus high-fat/low-
polysaccharide diets [or by bariatric (gastric
bypass) surgery]. The results, coupled with co-
incident assessments of energy extraction from
the diet, should provide a proof-of-concept test
of whether differences in the composition of
the microbiota are associated with differences
in gut bioreactor efficiency (and predisposition
to obesity).
Lessons that have been learned by envi-
ronmental engineers who study how to op-
timize the efficiency of man-made anaerobic
bioreactors (table S3) suggest that these enu-
meration studies should also include mem-
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bers of archaea. Thermodynamics dictates
that the energy obtained from substrate con-
versions will be higher if low concentrations
of products are maintained (33, 34). In the
human gut, methanogenic archaea provide
the last microbial link in the metabolic chain
of polysaccharide processing. Bacteria de-
grade polysaccharides to short-chain fatty
acids, CO2, and hydrogen gas. Methanogens
lower the partial pressure of hydrogen by gen-
erating methane, and thereby may increase
microbial fermentation rates. Defining the rep-
resentation of mesophilic methanogens in the
colonic microbiota of individuals, sequencing
their genomes [as we are currently doing with
Methanobrevibacter smithii, a prevalent isolate
from the human colon (35)], and characteriz-
ing archaeal-bacterial syntrophy in simplified
gnotobiotic mouse models consuming differ-
ent diets should provide a starting point for
defining the role of archaea in shaping the
functional diversity, stability, and beneficial
contributions of our distal gut microbiota.
Devising ways for manipulating archaeal pop-
ulations may provide a novel way for inten-
tionally altering our energy balance.
Looking to the Future
A comprehensive 16S rRNA sequence–based
(bacterial and archaeal) enumeration of the
microbiotas of selected humans, representing
different ethnic groups, living in similar or
distinct milieus, would provide an invaluable
database for studying normal and diseased
populations (36). The concept of using the
microbiota as a biomarker of impending or
fully manifest diseases within or outside of
the GI tract and for monitoring responses to
therapeutic interventions needs to be explored.
Several groups are embarking on meta-
genome sequencing projects to define gene
content in the human gut microbiome. If we
view ourselves as being a composite of many
species, this represents a logical continuation
of the Human Genome Project. A complemen-
tary approach to metagenomic analysis is to
determine genome-level diversity among bac-
terial populations belonging to a specific ge-
nus or species residing within a defined gut
habitat of a single individual or a few indi-
viduals. Members of Bacteroides provide a
natural experiment for examining the impact
of habitat on genome content since they have
yet to be encountered in any environment
other than animal GI tracts. Figure 1C illus-
trates how a collection of just 29 isolates phe-
notyped as B. thetaiotaomicron provided a
broad range of 16S rRNA sequences, includ-
ing several new species. We are close to pro-
ducing finished genome sequences for two
prominent members of the colonic microbiota,
B. vulgatus and B. distasonis (37). B. fragilis,
a less prominent member, has recently been
sequenced (38, 39). The results will allow us
to ask how evolutionary history relates to
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THE INNER TUBE OF LIFE
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genome content and what constitutes a
minimal Bacteroides genome.
We also need to obtain a direct view of
how the metabolites originating from the
microbiome influence host physiology. This
will be a formidable task, requiring new tech-
niques for measuring metabolites generated
by single and defined collections of symbionts
during growth under defined nutrient condi-
tions in single-vessel chemostats, in more
elaborate mechanical models of the human
gut, and in vivo after colonization of specified
habitats of the intestines of gnotobiotic mice.
The results should help formulate and direct
hypothesis-based investigations of the micro-
biota’s ‘‘metabolome’’ in humans.
Databases that connect molecular data
with ecosystem parameters are still rare (40).
A human intestinal microbiome database is
needed to organize genomic, transcriptomic,
and metabolomic data obtained from this
complex natural microbial community, and
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would provide a substrate for generating test-
able hypotheses.
Finally, just as microbiotas have coevolved
with their animal hosts, this field must co-
evolve with its academic hosts and their abil-
ity to devise innovative ways of assembling
interactive interdisciplinary research groups
necessary to advance our understanding.
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Work cited from the authors’ lab is supported by the
NIH and NSF. F.B. and J.L.S. are supported by
postdoctoral fellowships from the Wenner-Gren
and W. M. Keck Foundations, respectively.
Supporting Online Material
www.sciencemag.org/cgi/content/full/307/5717/1915/
DC1
Materials and Methods
Tables S1 to S3
References
10.1126/science.1104816

REVIEW

Immunity, Inflammation, and Allergy in the Gut

Thomas T. MacDonald1*. and Giovanni Monteleone2

The gut immune system has the challenge of responding to pathogens while re- and sample commensal and pathogenic gut
maining relatively unresponsive to food antigens and the commensal microflora. In bacteria (4, 5). The gut epithelial barrier there-

Downloaded from http://science.sciencemag.org/ on January 6, 2018

the developed world, this ability appears to be breaking down, with chronic in- fore represents a highly dynamic structure that
flammatory diseases of the gut commonplace in the apparent absence of overt limits, but does not exclude, antigens from
infections. In both mouse and man, mutations in genes that control innate entering the tissues, whereas the immune sys-
immune recognition, adaptive immunity, and epithelial permeability are all tem constantly samples gut antigens through
associated with gut inflammation. This suggests that perturbing homeostasis the FAE and DC processes.
between gut antigens and host immunity represents a critical determinant in the
development of gut inflammation and allergy. Commensal Bacteria in
Epithelial/Immune Cell Function
The gastrointestinal tract is the site where the system is the single layer of gut epithelium, in the Gut
divergent needs of nutrient absorption and the surface area of which is expanded to the Interaction of commensals with gut epithelium.
host defense collide: The former requires a order of 400 m2, largely because it is formed The gut epithelium itself can also directly
large surface area and a thin epithelium that into millions of fingerlike villi in the small sense commensal bacteria and pathogens; in-
has the potential to compromise host defense. bowel. Each epithelial cell maintains inti- tegral to this are the mammalian pattern rec-
Many infectious diseases involve the gut, and mate association with its neighbors and seals ognition receptors (PRRs), which recognize
the investment by the gut in protecting itself the surface of the gut with tight junctions. In conserved structures of bacteria and viruses
is evident in the abundant lymphoid tissue the upper bowel, the bulk of the antigen ex- and generally activate pro-inflammatory path-
and immune cells it harbors. In westernized posure comes from diet, whereas in the ileum ways alerting the host to infection (6). Two
countries, most infectious diseases of the gut and colon, the additional antigenic load of an different classes of PRRs are involved. The
are largely under control, yet gastrointesti- abundant and highly complex commensal mi- Toll-like receptors (TLRs) are usually asso-
nal food allergies and idiopathic inflammatory croflora exists. ciated with cell membranes and have an ex-
conditions have dramatically increased; in other Nevertheless, the gut epithelial barrier does ternal leucine-rich repeat (LRR) recognition
words, we now have inflammation without not completely prevent lumenal antigens from domain and an intracellular interleukin-1
infection. Although the reason for this remains entering the tissues. Thus, intact food proteins receptor (IL-1R)–like signaling domain (7).
unknown, a prevailing notion is that the ab- can be detected in plasma (1), and a few gut The nucleotide-binding oligomerization do-
sence of overt gut infection has upset the bacteria can be detected in the mesenteric main (Nod) molecules, Nod1 and Nod2 [also
balance between the normal bacteria that lymph nodes draining the gut of healthy known as CARD4 and CARD15 (caspase
colonize the healthy gut and the mucosal im- animals (2). Antigens can cross the epithelial activation and recruitment domain)], are
mune system. surface through breaks in tight junctions, per- present in the cytosol of epithelial cells and
haps at villus tips where epithelial cells are immune cells. These proteins also have LRRs
The Gut Epithelial Barrier shed, or through the follicle-associated epithe- at the C terminus, a Nod domain, and CARD
The primary cellular barrier of the gut in pre- lium (FAE) that overlies the organized lymph- domains at the N terminus (8). There is abun-
venting antigens encountering the immune oid tissues of the intestinal wall (3). Peyer’s dant evidence that signaling through Nod or
patches (PP) in the small bowel are aggre- TLR activates transcription factor NF-kB, lead-
1 gates of lymphoid tissue numbering È200 in ing to pro-inflammatory gene expression (7, 8)
Division of Infection, Inflammation, and Repair, Uni-
versity of Southampton School of Medicine, South- the average adult, although tens of thousands TLR1 to TLR9 and Nod1 and Nod2 are
ampton General Hospital, Southampton, SO16 6YD, of much smaller individual follicles also line each expressed by gut epithelial cells (6, 9).
UK. 2Dipartimento di Medicina Interna e Centro di the small bowel and colon. FAE contains spe- Nod1 and Nod2 recognize slightly different
Eccellenza per lo Studio delle Malattie Complesse e cialized epithelial cells termed M cells whose muropeptide motifs derived from bacterial pep-
Multifattoriali, Università Tor Vergata, Rome, Italy.
function is to transport lumenal antigens into tidoglycans (6), which suggests that they sense
*Present address: Barts and the London School of the dome area of the follicle (3) (Fig. 1). intracellular infection or attempted bacterial
Medicine and Dentistry, Turner Street, London E1
2AD, UK.
Antigen-presenting dendritic cells (DC) also subversion of epithelial cells (10). TLRs recog-
.To whom correspondence should be addressed. send processes between gut epithelial cells nize many different components of bacteria
E-mail: t.t.macdonald@qmul.ac.uk without disturbing tight junction integrity and viruses. For example, TLR4 recognizes

1920 25 MARCH 2005 VOL 307 SCIENCE www.sciencemag.org

Host-Bacterial Mutualism in the Human Intestine
Fredrik Bäckhed, Ruth E. Ley, Justin L. Sonnenburg, Daniel A. Peterson and Jeffrey I. Gordon

Science 307 (5717), 1915-1920.

DOI: 10.1126/science.1104816

Downloaded from http://science.sciencemag.org/ on January 6, 2018

ARTICLE TOOLS http://science.sciencemag.org/content/307/5717/1915

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